PROJECT SUMMARY The long-term goal of this project is to understand why some individuals live longer or healthier lives than others. This will provide a foundation for the development of new diagnostics to identify at-risk individuals and therapeutic interventions to improve human aging. Neither genetics nor the environment can fully account for the variability in lifespan or healthspan among individuals. Here, we will use the simple animal C. elegans to study non-genetic variability in aging, which is often disregarded as ?biological noise?. We hypothesize that there is signal in this noise: that inter-individual differences in lifespan and healthspan are the result of regulated processes early in life that can be understood, predicted, and altered. To study inter-individual variability, we developed an innovative imaging system in which isolated, genetically identi- cal C. elegans can be reared in identical environments, allowing for lifelong measurement of gene expres- sion and physiological function. We will use this system to determine factors that distinguish long-lived and healthy individuals from their short-lived and unhealthy ? yet genetically identical ? siblings. In Aim 1, we will use our imaging system to characterize regulatory genes whose expression levels deter- mine future lifespan and healthspan. Such regulators are exciting because they have maximum ?leverage?: small changes in these genes, in wild-type conditions, can produce large effects on lifespan and health. In preliminary work, we identified nine microRNAs that are predictive of future lifespan. One of these, mir-71, regulates key components of the insulin/IGF-1-like signaling pathway (IIS). We will now determine if these microRNAs influence individual healthspan in addition to lifespan, and will identify other regulatory genes that predict lifespan and/or healthspan. We will determine the longevity pathways that each gene acts on, and place these genes into pathways to define the regulatory network that governs individual aging. Aim 2 will examine the relationship between lifespan and healthspan. In both humans and C. elegans, it is controversial whether extended lifespan is generally accompanied by a proportional extension of healthspan. We recently showed that this is not the case among wild-type C. elegans: longer-lived individ- uals spend a smaller fraction of life in good health. We will now use our novel imaging system to quantita- tively examine how physiological health changes over time in mutants and in other lifespan-altering condi- tions. With these data we will: define mathematical rules that govern aging, identify exceptional conditions that alter those rules, and determine which individuals respond best to lifespan-extending interventions. The overall impact of this work will be: (1) to identify molecular mechanisms that underlie extended lifespan and health; (2) to improve our basic knowledge of the relationship between lifespan and healthspan; and (3) to discover conditions that alter the tradeoff between lifespan and healthspan that we observe in wild type. This will help identify biomarkers to predict ? and targets to influence ? future lifespan and health.